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Deuterated pyrimidine compound, preparation method, pharmaceutical composition, preparation and application

A technology of deuterated pyrimidine and pharmaceutical preparations, which can be used in drug combination, organic chemistry, anti-tumor drugs, etc., and can solve the problems of instability, toxic and side effects of AZD9291

Inactive Publication Date: 2018-10-19
纽瑞森生物科技(北京)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the prior art, the drug metabolism research on AZD9291 (M.R.V.Finlay, et al, J.MedChem.2014, 57, 8249) shows that AZD9291 is unstable in animals and humans, and will have certain toxic and side effects. If AZD9291 can be Improved to increase its stability, it can be expected that its toxic side effects will be reduced

Method used

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  • Deuterated pyrimidine compound, preparation method, pharmaceutical composition, preparation and application
  • Deuterated pyrimidine compound, preparation method, pharmaceutical composition, preparation and application
  • Deuterated pyrimidine compound, preparation method, pharmaceutical composition, preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] The preparation of embodiment 1 formula (1) compound

[0084]

[0085] 1. Synthesis of intermediate a

[0086]

[0087] Under the protection of argon, add indole-d7 (3g, 24mmol) and 20mL anhydrous THF (tetrahydrofuran) to a 100mL three-necked flask successively, cool down to 0°C, and add sodium hydride (NaH) (60%, dispersed in Mineral oil) (1.4g, 36mmol), stirred and reacted at 0°C for 30min, then added deuterated iodomethane (4.2g, 29mmol) dropwise, heated to room temperature and reacted for about 3 hours. After the reaction, cool to 0°C, add 20 mL of saturated NH4Cl aqueous solution to the reaction mixture, extract with ether (30 mL×3), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and spin dry to obtain a crude product.

[0088] The obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether (PE): ethyl acetate (EA) = 100:0-90:10), and the obtained eluent was spin-dried to o...

Embodiment 2

[0109] The preparation of embodiment 2 formula (2) compound

[0110]

[0111] When preparing the compound of formula (2), in addition to replacing the compound of formula (C1) (N, N'-trimethylethylenediamine) in step 4 in the above example 1 with the compound of formula (C2) (N1 , N1-bis(methyl-d3)-N2-methyl-1,2-diamine), other steps refer to Example 1.

[0112] The prepared compound is a light yellow solid. LC-MS: 516.9.

[0113]

[0114] A hydrogen NMR data is: 1 H-NMR: (300MHz, DMSO-d 6 ,ppm)2.30(m,2H),2.73(s,3H),2.90(m,2H),3.87(s,3H),7.05(s,1H),7.23(m,1H),7.91(s,1H ), 8.33(m,1H), 9.15(s,1H), 10.22(s,1H). It is proved that the obtained compound is the compound of formula (2).

Embodiment 3

[0115] The preparation of embodiment 3 formula (3) compound

[0116]

[0117] When preparing the compound of formula (3), in addition to replacing the compound of formula (B1) (4-fluoro-2-methoxy-5-nitroaniline) in step 3 in the above-mentioned embodiment 1 with the following formula (B2 ) compound (4-fluoro-2-(methoxy-d3)-5-nitroaniline), other steps refer to Example 1. The prepared compound is a light yellow solid. LC-MS: 513.9.

[0118]

[0119] A hydrogen NMR data is: 1 H-NMR: (300MHz, DMSO-d 6 , ppm) 2.22 (s, 6H), 2.31 (m, 2H), 2.73 (s, 3H), 2.90 (m, 2H), 7.05 (s, 1H), 7.23 (m, 1H), 7.91 (s, 1H ), 8.33 (m, 1H), 9.15 (s, 1H), 10.22 (s, 1H). It is proved that the obtained compound is the compound of formula (3).

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Abstract

The invention provides a deuterated pyrazolopyrimidine compound, pharmaceutically acceptable salt, stereoisomer, a prodrug molecule or a solvate thereof, a preparation method of the deuterated pyrazolopyrimidine compound, a pharmaceutical composition, a preparation and application. The compound or salt or a pharmaceutical composition and a pharmaceutical preparation thereof have an inhibitory effect on variation forms of EGFR (Epidermal Growth Factor Receptor) protease; production of multiple tumor cells can be effectively inhibited, and the deuterated pyrazolopyrimidine compound can be used for preparing anti-tumor medicines and the like; compared with AZD9291, the compound has the advantages that concentration and stability of the medicine in blood can be improved, so that the use dosageof the medicine can be reduced, and the toxic and side effects of the medicine are reduced.

Description

technical field [0001] The present invention relates to the field of chemistry and medicine, more specifically, to a deuterated pyrimidine compound, a preparation method, a pharmaceutical composition, a preparation and an application. Background technique [0002] AZD9291 (Osimertinib, Osimertinib) is the third epidermal growth factor receptor EGFR (epidermal growth factor receptor, EGFR) inhibitor, EGFR is a member of the epidermal growth factor receptor (HER) family. Small cell lung cancer has a good inhibitory effect and has become a second-line treatment for lung cancer patients who develop resistance to Gefitinib, Erlotinib or Afatinib. [0003] In the prior art, the drug metabolism research on AZD9291 (M.R.V.Finlay, et al, J.MedChem.2014, 57, 8249) shows that AZD9291 is unstable in animals and humans, and will have certain toxic and side effects. If AZD9291 can be Improved to increase its stability, it can be expected that its toxic side effects will be reduced. Con...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/506A61P35/00
Inventor 郭建华
Owner 纽瑞森生物科技(北京)有限公司
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